Ischemia / reperfusion (I/R) injury to the lung is accompanied by endothelial activation, leukocyte adhesion and neutrophil accumulation. Clinical experience also indicates that pulmonary injury is often accompanied by a transient deficit in cardiac performance. We hypothesize that the cascade of inflammatory activation initiated by I/R injury to the lung is ultimately responsible for the cardiac dysfunction observed in this setting. We propose that whole animal experiments employing a complementary set of pharmacologic and genetic approaches will serve to elucidate the role of inflammation in cardiac dysfunction after lung I/R injury and to identify effective treatment strategies. In preliminary studies, we have developed a mouse model of lung I/R injury and have used cardiac magnetic resonance imaging (MRI) to evaluate cardiac function in intact mice. In this project, the role of inflammatory activation after I/R injury to the lung will be elucidated using specific pharmacologic agents, genetically-manipulated mice and adoptive transfer techniques. A multidisciplinary approach will be used that spans the fields of surgery, biomedical engineering, radiology, cardiovascular physiology, pharmacology, immunopathotogy, cell biology and molecular genetics. The specific aims are to: 1) Characterize the duration and extent of inflammatory activation in the mouse lung and heart after pulmonary. I/R injury, We have recently shown that an anti-inflammatory agent can reverse the cardiac dysfunction that results from I/R injury to the lung. Using a mouse model, we will test the hypotheses that i) I/R injury to one lung induces inflammatory activation in the other lung, and ii) the cardiac dysfunction that results from I/R injury to the lung is due to inflammatory activation. 2) Define the signaling pathways responsible for cardiac dysfunction after lung injury. T-cell deficient mice and adoptive transfer techniques will be used to test the hypothesis that T-cells participate importantly in the cardiopulmonary response to lung injury. Furthermore, we hypothesize that cardiac dysfunction as a result of I/R injury to the lung will be attenuated by agents that interfere with inflammatory activation. 3) Characterize the effects of A2a-adenosine receptor stimulation on myocardial energetics after I/R injury to the lung using 31P NMR spectroscopy. We hypothesize that A2A-adenosine receptor stimulation will improve myocardial energetics in mice subjected to pulmonary I/R injury.